HCV infection poses a significant public health problem worldwide and is recognized as the major cause of non-A, non-B hepatitis. The etiologic agent of hepatitis C, the hepatitis C virus (HCV) is widely regarded as a member of the Flaviviridae family and category of arboviruses, having a single-stranded positive-sense RNA genome encoding a polyprotein of approximately 3000 amino acids.
Although HCV infection resolves itself in some cases, the virus establishes chronic infection in up to 80% of the infected individuals, and may persist for decades. It is estimated that about 20% of these infected individuals will go on to develop cirrhosis, and 1 to 5% will develop liver failure and hepatocellular carcinoma (Seeff, et al. 1999, Am. J. Med . 107:10S-15S; Saito, et al. 1990, Proc. Natl. Acad. Sci. USA, 87:6547-6549; WHO, 1996, Weekly Epidemiol. Res., 71:346-349). Chronic hepatitis C is the leading cause of chronic liver disease, and the leading indication for liver transplantation in the United States. The Centers for Disease Control and Prevention estimate that hepatitis C is currently responsible for approximately 8,000 to 10,000 deaths in the United States annually. This number is projected to increase significantly over the next decade. Unfortunately, development of effective and safe vaccines for HCV has been impeded by the relatively high immune evasion, probably due to a comparably high degree of heterogeneity of this virus. Still further, mechanistic studies of HCV replication have been hindered by the lack of an in vitro cell culture system and a validated small animal model as an alternative to the chimpanzee.
Currently, the most widely prescribed HCV antiviral therapy is the combination of interferon-alpha 2b (IFN-alpha-2b, Intron A) and ribavirin, a treatment capable of suppressing viral titers in about 40% of chronically infected patients. However, immunogenicity and relatively low serum half-life times of interferon-alpha 2b have limited treatment success, at least in some patients. To overcome at least some of the difficulties with immunogenicity and relatively low serum half-life time, interferon-alpha 2b has been coupled to polyethylene glycol. Use of such modified (pegylated) interferon in HCV therapy has significantly improved the clinical outcome for numerous patients. However, there is still a significant portion of patients in which viral propagation persists, even when Ribavirin is coadministered with pegylated interferon.
Alternative proposed and experimental pharmaceutical compositions for treatment of HCV infections include various nucleoside analogs. Exemplary compositions are described in WO 01/90121 to Novirio, WO 02/57425 to Merck, or WO 02/100354 to Ribapharm. While some of these compositions may have an antiviral effect to at least some degree, various disadvantages remain. Among other things, selectivity of such compounds for the viral polymerase may be less than desirable. Other potential disadvantages may include poor phosphorylation to the corresponding nucleotide (or nucleotide analog).
Furthermore, certain phosphonate nucleoside analogs are known to exhibit significant and selective antiviral effect. For example, 9-(2-Phosphonylmethoxyethyl)adenine (PMEA) is a potent antiviral agent against the hepatitis B virus (see e.g., U.S. Pat. Nos. 4,659,825, 4,724,233 or 4,808,716). However, PMEA is also extremely toxic and therefore has failed to provide a viable drug. In another example, 3′-Azido-3′,5′-dideoxythymidine-5′-methylphosphonic acid diphosphate showed promising antiviral effects against the human immunodeficiency virus (HIV), but exhibited relatively poor selectivity and is generally difficult to administer, specifically to infected cells (see e.g., J. Med. Chem. 1992 Aug. 21;.35 (17):3192-6). Still further, Watanabe et al. describe in published U.S. Patent Application US 20020055483 selected 2′,3′-substituted nucleosides that may include a phosphonate moiety as therapeutic molecules for treatment of hepatitis B, C, and D, or proliferative disorders. However, they report only a therapeutic effect against HBV. In still further known examples, (see e.g., U.S. Pat. Nos. 5,142,051, 5,302,585, 5,208,221, or 5,356,886) various acyclic phosphonate nucleoside analogs are presented with various pharmacological effects. However, such compounds are frequently difficult to synthesize and/or exhibit less than desirable (if any) antiviral activity against HCV.
In yet further examples, inorganic phosphonates (e.g., Foscarnet) have been employed to treat HBV infection as described in U.S. Pat. No. 6,495,521 to Horwitz, while various pyrophosphate analogs were shown to exhibit antiviral effect as described by McKenna et al in U.S. Pat. No. 6,444,837. However, despite relatively promising antiviral activity of such compounds against certain viruses, inorganic phosphonates and pyrophosphate analogs appear to exhibit less than desirable (if any) antiviral activity against HCV.
Therefore, although various compounds and methods are known in the art to treat HCV infection, all or almost all of them suffer from one or more disadvantages. Consequently, there is still a need for improved compounds and methods to treat viral infections, and particularly HCV infections.